N-allyl-and n-butenyl-hydrantoic acid



Patented at. 25,1953

UNITED srA'rss PATENT x-aun nm fggrmmmmm tion of New York No Drawing.

30, 1949, Serial No. 13

2592,41 dated til this app l'ica OFFICE N. Y.. lllsnor to I. Yorh-N.Y.,am

Original application November gees, now Patent No.

1952. Divided lllll tion December 28, 1951, Serial no.

2 Ohms- (ol. 260-534) This invention relates new therapeutically active organic mercurial compounds and has particular relation to organic mercurial compounds distinguished by diuretic activity and relatively low toxicity. The invention also relates to the methods of preparing these new compounds. 7

The known organic mercurial diuretics posass a common relationship, in which the mercury is bound to a carbon atom of an aliphatic lateral chain and they also possess a solubilizing carboxyl group. i Y

The main object of this invention is to provide new mercury compounds by the introduction of mercury into new organic compounds which contain at least one unsaturated group, consist of an alkyl group, a ureido or guanido group and a carboxyl group and have the general formula wherein It stands for allyl or butenyl and X stands for O or NH.

Another object of the present invention is to provide said new organic compound by the re- N action of glycine (amidoacetic acid) able organic reactants.

It is also an objector this invention to convert the abovementioned new mercury compounds inwith suitto theophylline, theobromine or sodium succinimide derivative and to solubilize the compounds embodying the invention by forming their salts with an alkali metal having an atomic weight below 56.

Other objects of the invention will be apparent from the appended claims and the following specification which describes by way of example some preferred embodiments of the invention.

The abovementioned neworganic compounds can be prepared according to the following reactions: a

R.NC=O HzN-CHrCOOH nnmo-nmclncoon omen nnnoennmncmooon wherein R stands for allyl or butenyl. In order to convert the compounds thus obtained into mercuratedderivatives suitable for use as a diuretic, said compound is reacted in an aqueous or alcoholic medium with a mercury salt of the Iormula Z-Hg-Z or z-Hg--W, either as such 55 tent of 44.5%.

or freshly formed, Z meaning a group capable of forming a metal salt, such as acetoxy or chloride group and W an alkoxy or hydroxy group. The general formula of probably wherein R stands for H or CH3: Y stands for H, 7 methyl, ethyl, propylor isopropyl; W1 stands for Example 1 8.3 grams mole) of allyl isocyanate mixed with 50 cc. of distilled water containinga small amount of potassium hydroxide or sodium hydroxide, are mixed with 5 grams (0.066 mole) of glycine in 25 cc. of water, and heated on a steam bath for about 30 minutes. The amount of alkali must be suflicient for obtaining an alkalinity of about pH 9 to 12 in the reaction incdium. The mixture is then cooled in an ice bath. A white solid begins to crystallize and is filtered after standing for about two to three hours. The crystalline product thus obtained is N-a1lyl-hydantoic acid; it has a nitrogen content of 17.5% and melts with decomposition at Example II 0.1 mole of the N-allyl-hydantoic acid is mixed with about 1.5 liters 01' hot methanol and to it is added a solution of 0.1 mole of mercuric acetate in about cc. of hot methanol. The mixture is stirred and allowed to sit at room temperature'for about 24-48 hours andthe solvent is then evaporated under reduced pressure. The remaining white powd melts with decomposition at 178-180 Gran shows a mercury conthe mercui'ated product is The chemical reactions in the above Examples I and II are as follows:

N-allyl-hydantoic acid CHI-43 HCH:-NH-' -NHCH|C 0 0H 0 C H gCHiC 0 N- (gamma-methoxy-beta-acetoxymercuri-propyl) -hydantoic acid By using ethanol, propanol, or isopropanol in place of the methanol, the appropriate analogous alkoxy derivative is obtained. These derivatives melt with decomposition at the following temperatures:

. C. Ethoxy derivative 176-179 Propoxy derivative 171-174 Isopropoxy derivative 1691'71 If the reaction between the N-ailyl-hydantoic acid and mercuric acetate is carried out in aqueone medium, instead oithe alkoxy derivative the analogous hydroxy derivative is obtained.

' Example I]! 0.14 mole of butenyl isocyanate mixed with 50 cc. of distilled water, containing a small amount of potassium hydroxide or sodium hydroxide, are mixed with 0.1 mole of glycine in 40 cc. of distilled water and heated on a steam bath for about 30 minutes. The amount of alkali must be sumposition at 253-256 C. and has a nitrogen concient for obtaining an alkalinity of about pH 9 r to 12 in the reaction medium. The mixtureis then cooled in an ice bath and is filtered after standing for about two to three hours. The

product formed is N-butenyl-hydantoic acid. It

contains 16.0% of nitrogen and melts with decomposition at 150-154 C. The reaction takes place according to the following scheme:

CHECH=CHCH1NC=0 mmcmcoon Butenyl isocyanaie Glycin 0 CH -CH=CHOHr-NH NH.CH1C00H N butenyl hydantoio acid Example IV v 0.1 mole of the N-butenyl hydantoic acid is mixed with about 1.5 liters of hot methanol and to it is added a solution of 0.1 mole of mercuric acetate in about 100 cc. of hot methanol. The

mixture is stirred and allowed to sit at room temperature for about 24-48 hours. Upon evaporation of the solvent under reduced pressure,

the mercurated compound is obtained as a white I powder of the following probable formula:

0.1 mole of S-methyl-N-allyl-thiouronium salt is mixed with about 50 cc. of 2 normal aqueous sodiumhydroxide or potassium hydroxide solution and placed in an ice bath. A hot solution of 10 grams of glycine in about 50 cc. of distilled water is added rapidly and the mixture stirred. when the temperature of the mixture is about '25" c., the is removed from the ice bath and about cc. of ether are added. After sitting at room temperature for 24 hours, the mixture ischilled for-about two hours and filtered with the aid of suction. A crystalline substance is obtained, which is purified by recrystallization from hot water. This substance, which is N-allyl-guanido-acetic acid, melts with decomtent of 27.2%.

The reaction takes place according to the following scheme:

mromon=om S-methyl-ailyl-thiourea Glycin CH:=G H-CHaNHd (:NH)NH.CH|C 0 O H N-allyl-guanido-acetic acid Example VI In order to convert the N-allyl-guanido-acetic acid obtained in Example V into a mercurated compound, 0.1 mole of the latter is mixed with about 1.5 liters of hot methanol and a solution of 0.1 mole of mercuric acetate in about 100 cc. of hot methanol under stirring. The mixture is allowed to sit at room temperatur for 24-48 hours and the solvent is then evaporated under reduced pressure. The mercurated compound,

which is obtained as a white powder, has the following probable formula:

CHPCH-CHQHCCNHHIHIZHCOOH 0 Hi 5 C Etc 0 N- (gamma-methoxy-beta-acetoxymercuri-propyl) -guanidoacetic acid This compound melts with decomposition at -188 C., while the corresponding ethoxy compound, which is obtained in a similar manner with ethylalcohol, melts with decomposition at 183-185 C.

Example V1 0.1 mole of S-methyl-N-butenyl-thiouronium salt 'is mixed with about 50 cc. of 2 normal aqueous sodium hydroxide or potassium hydroxid solution and placed in an ice bath. A hot solution of 10 grams of glycine in about 50 cc. of distilled water is rapidly added and the mixture stirred. When the temperature of the reaction mixture is about 25 C., the mixture is removed from the ice bath and about 100 cc. of ether' are added. The mixture is kept at room temperature for 24 hours, then chilled for about two hours and then 'flltered under suction. The filtration residue is recrystallized from hot water. of the formula CH2=CHCH2-CH:NHC( :NH) NI-LCHzCOOI-I N-butenyl-guanido-acetic acid Example VIII It is a compound assess? The modification of the mercuration reaction described in Example 11 may be also applied to the mercuratlon of the compounds obtained according to Examples 111, V and VII. Thus, ethanol, propanol, or isopropanol may be used instead of methanol under substantially equal conditions in order to obtain the appropriate analogous alkoxy derivative, and the analogous hydroxy derivative is formed it the reaction with mercuric acetate is carried out in aqueous medi- Example IX By using an alkoxy mercuric acetate instead of the mercuric acetate in Examples II. IV. VI

and VIII, water may be substituted for one half the volume of the alcohol used as a solvent, to obtain the same products.

Furthermore, the chloromercuri derivative may be obtained when the mercuratlng salt contains an atom of chlorine, i. e. when for example methoxy mercury chloride is used for mercuration or when the mercurated compound is treated with a molar excess of sodium chloride solu tion.

. Example X 0.1 mole of any of the mercurated compounds obtained according to Examples II, III, VI, VIII or D! is mixed with 0.1 mole of sodium theophylline in about 300 cc. of distilled water. The'mixture is stirred for about one hour and the solvent is then evaporated under reduced pressure. The evaporation residue is washed with a small amount of warm water and the washed product is dried. The resultinz white powder consists of a compound corresponding to the general wherein It stands for H or CH1; Y stands for H, methyl, ethyl, propyl or isopropyl; R" stands for theophylline, and X stands for O or NH.

For example by reacting the N-(gammamethoxy beta acetoxy mercuri propyl) hydsntoic acid obtained according to Example 11, with theollhylline. N-(gamma-methox'y-betatheophylline-mercuri-DmyD-hydantoic acid is obtained. This derivative melts with decomposition at PIP-178' 0., while the theophylline derivative obtained from the analogous ethoxy compound melts with decomposition at 173'475'. C. The theophylline derivative of the N-(gammamethoxy-beta-ace -propyl) -guanidom acid melts with decomposition at 181'- By substituting in the above procedure sodium theobromine or sodium succinimide. the appropriate derivatives are formed, 1. e. compounds of the above Ieneral formula, in which R" stands for theobromine or luccinimide.

prising reacting a compound of the formula,

Number Example I! 0.1 mole of the dried product obtained in one of the above Examples II, IV, VI, VIII, IX or X. is stirred with an exact equivalent solution of aqueous sodium hydroxide or alcoholic sodium methylate. The solution is then evaporated under reduced pressure and the sodium salt of the compound used as starting material is obtained. These salts are freely soluble in water.

It will be understood that the present invention is not limited to the specific substances. steps and other details described above and may be carried out with various modifications. For example, instead of glycine other compounds of the general formula HzN-(CHaMCOOH. wherein n denotes 2, 3 or 4, can be used in order to obtain the appro riate analogous compounds embodying the present invention. These and other modifications can be made without departing iron the scope of the invention as defined in the appended claims. a

The compounds obtained according to the present invention ar therapeutically active mercurials and are particularly distinguished by their diuretic activity and relatively low toxicity.

Reference is made to my co-pending' application Ser. No. 180,383, flied November-'80, 1049, of

which this is a division.

What is claimed is: 1. A new compound of the general formula wherein R: is selected from the group consisting of allyl and butenyl radicals, X is selected from the group consisting of 0 and NH, and Me is selected from the group consisting of H and atoms of alkali metals with an atomic weight below 50. f 2. Aprocessforproducingaoompoundotthc ormula 1 wherein R: is selected from the group consisting of allyl and butenyl radicals. saidprocess com- Ra-NC.=0, wherein Re has the meaning as delined above, with g y i under heating at to C. in aqueous reaction medium at a pH of 9 to 12.

References Cited in the me of thlsLpatent um'rm s'rs'rss PATENTS Name Date 2.51am Gluesenkamp Oct. 2:. mi 2.502.411:

Halpern Apr. l, 

1. A NEW COMPOUND OF THE GENERAL FORMULA 